1. Field of the Invention
This invention relates to methods of treating and managing kinetoplastid infections by administering artemisimins and artelinic acid.
2. Brief Description of Related Art
Trypanosomiasis is a re-emerging [1-3] tropical infectious disease that poses a real challenge to public health countermeasures. According to the World Health Organization (WHO) [4], about 36 sub-Saharan countries in West, Central, and East Africa and some 22 Latin countries in Central and South America delimit its geographic prevalence zone, thus, leading to the establishment of two distinct manifestations of the disease: African trypanosomiasis and American trypanosomiasis.
Trypanosoma species pathogenic to human beings and domestic animals in Africa, cause one of the world's most neglected tropical infections—African trypanosomiasis [3]. Nearly eliminated in the 1960s, African trypanosomiasis has been making an alarming comeback due to civil wars, population displacements, and the collapse of public health systems mainly due to political instability (www.accessmed-msf.org/documents/ssfactsheet.pdf) [1]. Human African trypanosomiasis (HAT) threatens 60 million [1,3-6] men, women, and children among, principally, the rural populations, but actually even the citadin populations, in countries of high endemicity such as Angola, southern Sudan, the Democratic Republic of Congo, and northern Uganda. The incidence rate in HAT is estimated between 300,000-500,000 cases annually [3-6] and only 3 to 4 million people at risk are under regular medical surveillance (http://www.who.int/inf-fs/en/fact259.htlm). In animal African trypanosomiasis (AAT), the infection threatens about 50 million head of cattle with an estimation of 3 million deaths per year in livestock (http://www.fao.org/ag/againfo/programmes/en/paat/disease.htlm).
American trypanosomiasis (“Chagas disease”) occurs mainly in countries such as Brazil, Chile, Mexico, Uruguay, Paraguay, Bolivia, and Argentina [10, 11]. Over 13 million persons in the Southern American region are at risk of infection and the annual incidence rates of the disease reaches 200,000 cases in 15 endemic countries [10]. The bloodstream protozoan Trypanosoma cruzi [10-12] is the etiologic agent of Chagas disease.
Host-to-host transmission is mediated by blood-sucking triatomine bugs such as Triatoma infestans [11]. Moreover, blood transfusion and congenital transmission have been encountered, particularly, in humans [10]. These pathogens are all cyclically transmitted to mammalian hosts through the bite of haematophagus tsetse flies (Glossina morsitans, Glossina palpalis) [9] serving as vectors of the disease.
The consistent decimation of human populations and cattle by African trypanosomiasis has reached dramatic proportions and represents a social and economical obstacle for development [6,7]. In AAT, breeding animal losses are estimated to cost African farmers US$4.5 billion per year [8]. Bloodstream flagellated protozoan, members of the taxonomic genus Trypanosoma, are incriminated as the causative agents [1-7]. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense provoke human African trypanosomiasis (“sleeping sickness”) while Trypanosoma congolense, Trypanosoma simiae, Trypanosoma vivax and Trypanosoma brucei brucei cause animal African trypanosomiasis (“nagana”) [http://www.vet.uga.edu/vpp/gray_book/FAD/AAT.htm].
In the particular case of human African trypanosomiasis, the trypanosomes multiply in the blood and lymph glands of the infected persons, therefore, defining the first-stage of sleeping sickness [5,13]. The symptoms in this early stage are characterized by bouts of fever, headaches, skin itching, pain in the joints, gradual loss of weight, nausea and vomiting [6,9]. Later, in the second stage, the trypanosomes cross the blood-brain barrier and invade the central nervous system to cause sleeping sickness. Sleeping sickness is characterized by neurological disorders such as mental confusion, sensory disturbances and poor muscular coordination, and reversal of the circadian sleep/wake cycle (insomnia in the night, drowsiness in the daytime) [5,9,13,14] hence, the nickname “sleeping sickness”. In the absence of effective treatment, sleeping sickness invariably leads to death [3,6].
Control measures for African trypanosomiasis are directed either against the transmission vector through eradication of the tsetse fly, or against the causative pathogen, trypanosomes. Although vector control strategies had been effective in the past, they have been virtually abandoned because of their harmful effects on the environment [7]. Treatment of infected persons with the few available synthetic trypanocidal agents have shown significant drawbacks [15-17] related to high cost, host toxicity, limited oral bioavailability, and a requirement for hospitalization during the entire course of treatment. The emergence of drug resistance has also limited the choice and effectiveness of affordable agents in clinical use. Moreover, the type of treatment depends on the stage of the disease: hemolymphatic (first stage) or cerebral (second stage). Effectiveness in the second stage relies on the ability of the drug to cross the blood-brain barrier and reach concentrations high enough to kill the infective trypanosome. The four trypanocidal drugs, shown below [5,6,13] that have been clinically used up-to-date against sleeping sickness are, in chronological order—: Suramin (developed in 1921 against T. b. rhodesiense in the first-stage infection), Pentamidine (discovered in 1941 against first-stage T. b. gambiense infection), Melarsoprol (developed in 1949 against both human-infective Trypanosoma subspecies in cerebral infection), and Difluoromethyl ornithine (developed in 1981 as an alternative to Melarsoprol treatment failure in cerebral sleeping sickness). FIGS. 1a and b show the known trypanocidal drugs for early stage infection which are suramin and pentamidine, respectively. Suramin has no oral bioavailability and causes hemolysis and kidney disease. Pentamidine has no oral bioavailability, is an immunosuppressive and causes bleeding. FIGS. 1c and 1d show the known trypanocidal drugs for cerebral infection which are melarsoprol and difluoromethyl ornithine (DFMO), respectively. Melarsoprol has no oral bioavailability and causes tumors in the brain, blood in the urine and stomach pain. DFMO has no oral bioavailability and has a high susceptibility to resistance.
In the absence of prospective vaccine candidates for the disease, the limitations and drawbacks of these drugs emphasize the crucial need to develop new safe, effective and affordable drugs (trypanocides) against all forms of human and veterinary trypanosomiasis.
The Chinese plant Artemesia annua has been used to treat malaria for centuries. Research in the past three decades have uncovered artemisinin derivatives like artemisinin, dihydroartemisinin, artemether, artesunate that have played a critical role in the management of infectios caused by the multi-drug resistant malaria parasite, Plasmodium falciparum. Artemisinin has also been reported to be selectively active against cancer cells in vitro [39]. Utzinger et al. have demonstrated the use of artemisinin derivatives against tropical parasite species Schistosoma, responsible for schistosomiasis [40]. The effect of artemisinin and its derivatives on Leishmania major, another tropical parasite provoking leishmaniasis has also been reported [41]. However, the widespread use of this class of semi-synthetic artemisinin derivatives have been limited by the high cost of production, low bioavailability and long treatment regimens.
African, Asian and Amerindian societies have a rich tradition [17] in the use of plants for medical care. However, only few reports exist on the phytochemical treatment of sleeping sickness [17] and other kinetoplastid infections. Artemisinins have never before been used to treat human and veterinary trypanosomiasis. Until now, no experimental study has been carried out to establish the effectiveness of artemisinin or its derivatives on any Trypanosoma species.
The inventors are the first report on the trypanocidal potency of artemisinin and by extension, artemisinin-derived compounds, including artelinic acid.
Therefore, an object of the invention is to prepare a pharmaceutical composition containing artemisinin lead compounds from natural resources for the treatment of trypanosomiasis. Medicinal plants such as Artemesia annua have secondary metabolites of diverse molecular structures, physico-chemical properties, and pharmacological activities and offer an invaluable reservoir for new remedies.
Another object of the invention is to provide a cost effective treatment for kinetoplastid infections.
Another object of the present invention is to provide a method of treating humans and other mammals with kinetoplastid infections with artemisimin compounds such as artemisinin and artelinic acid.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.